Infection with Human Immunodeficiency virus (HIV)-1 can induce dementia for which currently no treatment is available. Research in our and other laboratories strongly suggests that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (M?) in the brain and impairment of neurogenesis. Beyond activation of M? and microglia, infection with HIV-1 triggers an innate immune response that includes production of interferons (IFNs). While IFNs are important for an anti-viral immune response, the lasting expression of IFN? in the HIV-1 exposed central nervous system (CNS) has been connected to cognitive impairment and inflammatory neuropathology. In contrast, IFN? has been implicated in the control of HIV infection in the brain. IFN? induces in M? and microglia natural ligands of the HIV coreceptor CCR5, such as MIP-1??? and RANTES, which inhibit HIV-1 infection. IFN? also induces the expression of nerve growth factor (NGF) and has pronounced anti-inflammatory effects. We found in preliminary studies that IFN? protected cerebrocortical neurons against neurotoxicity of HIV/gp120 while increasing baseline levels of RANTES. We also observed that RANTES and MIP-1? via CCR5 reduce the activity of the pro-inflammatory and stress-related p38 mitogen activated protein kinase (MAPK) and protect cerebrocortical neurons against neurotoxicity of HIV/gp120 in an Akt-dependent manner. Therefore, we propose to characterize the apparent neuroprotective effect of IFN? against toxicity of HIV/gp120 using in vivo and in vitro models. We hypothesize that IFN? can inhibit HIV/gp120 from inducing neuronal damage and impairing neurogenesis and compromising memory and cognition by a unique combination of mechanisms, comprising the induction of neuroprotective ?-chemokines and neurotrophic NGF. The long-term objectives are to find new potential treatments for HIV-associated dementia. The specific aims are: (1) To study in vivo whether IFN? prevents neuronal damage in a HIV/gp120 transgenic mouse model. (2) To assess in vitro whether the interaction of IFN? with microglia or M? suffices to prevent induction of HIV/gp120 neurotoxicity. (3) To investigate whether the interaction of IFN? with neurons and astrocytes suffices to protect the cells against HIV/gp120-induced neurotoxicity of microglia. For Specific Aim 1, IFN? will be administered via an intranasal route, which largely allows bypassing the blood brain barrier while delivering the drug to the brain. Memory and cognition-based behavioral performance, neuronal injury, neurogenesis and gliosis will be compared in IFN?- versus vehicle-treated HIV/gp120-transgenic mice. All three Specific Aims will test the premise that IFN? induces neuroprotective ?-chemokines and NGF, increases activity of Akt, reduces activity of p38 MAPK and glycogen synthase kinase (GSK) 32 and hyperphosphorylation of tau, and thus protects neurons and their dendrites and synapses from HIV/gp120-induced damage. We will also assess whether IFN? can preserve neurogenesis, memory and cognition and reduce gliosis in the presence of HIV/gp120. PUBLIC HEALTH RELEVANCE: HIV infection, AIDS and HIV-associated dementia remain a substantial public health concern and the proposed research aims at finding improved treatments by better understanding the disease process and the neuroprotective potential of the anti-viral cytokine interferon-?. Thus the proposed work will help to identify future therapeutic targets and thus new potential treatments for HIV-associated dementia via the analysis of intercellular and intracellular signaling mechanisms affected by the viral pathogen and host cytokines.